William MacNee

Length-dependent retention of carbon nanotubes in the pleural space of mice initiates sustained inflammation and progressive fibrosis on the parietal pleura

The fibrous shape of carbon nanotubes (CNTs) raises concern that they may pose an asbestos-like inhalation hazard, leading to the development of diseases, especially mesothelioma. Direct instillation of long and short CNTs into the pleural cavity, the site of mesothelioma development, produced asbestos-like length-dependent responses. The response to long CNTs and long asbestos was characterized by acute inflammation, leading to progressive fibrosis on the parietal pleura, where stomata of strictly defined size limit the egress of long, but not short, fibers. This was confirmed by demonstrating clearance of short, but not long, CNT and nickel nanowires and by visualizing the migration of short CNTs from the pleural space by single-photon emission computed tomographic imaging. Our data confirm the hypothesis that, although a proportion of all deposited particles passes through the pleura, the pathogenicity of long CNTs and other fibers arises as a result of length-dependent retention at the stomata on the parietal pleura.

An Official American Thoracic Society/European Respiratory Society Statement: Research questions in chronic obstructive pulmonary disease

BACKGROUND Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.

Prognostic value of variables derived from the six-minute walk test in patients with COPD: Results from the ECLIPSE study.

In addition to the six-min walk distance (6 MWD), other six-min walk test (6 MWT) derived variables, such as mean walk-speed (6MWSpeed), 6-min walk-work (6 MWW), distance-saturation product (DSP), exercise-induced oxygen desaturation (EID), and unintended stops may be useful for the prediction of mortality and hospitalization in patients with chronic obstructive pulmonary disease (COPD). We studied the association between 6 MWT-derived variables and mortality as well as hospitalization in COPD patients and compared it with the BODE index. A three-year prospective study (ECLIPSE) to evaluate the prognostic value of 6 MWT-derived variables in 2010 COPD patients. Coxs proportional-hazard regressions were performed to estimate 3-year mortality and hospitalization. During the follow-up, 193 subjects died and 622 were hospitalized. An adjusted Coxs regression model of hazard ratio [HR] for impaired 6 MWT-derived variables was significant referring to: mortality (6 MWD ≤334 m [2.30], 6MWSpeed ≤0.9 m/sec [2.15], 6 MWW ≤20000 m kg [2.17], DSP ≤290 m% [2.70], EID ≤88% [1.75], unintended stops [1.99]; and hospitalization (6 MWW ≤27000 m kg [1.23], EID ≤88% [1.25], BODE index ≥3 points [1.40]; all p ≤ 0.05). The 6 MWT-derived variables have an additional predictive value of mortality in patients with COPD. The 6 MWW, EID and the BODE index refine the prognosis of hospitalization.

Low sputum MMP-9/TIMP ratio is associated with airway narrowing in smokers with asthma

Asthmatic smokers have poor symptom control and accelerated decline in lung function. A reduced ratio of matrix metalloproteinase (MMP)-9/tissue inhibitors of metalloproteinases (TIMPs) in nonsmokers with asthma has been implicated in airway remodelling. We tested the hypothesis that sputum MMP-9 activity/TIMPs ratios are reduced in smokers compared with never-smokers with asthma and are associated with reduced lung function and altered computed tomography (CT) measures of airway wall dimensions. Lung function, airway dimensions by CT, and induced sputum concentrations (and activity) of MMP-9 and TIMP-1 and -2 were measured in 81 asthmatics and 43 healthy subjects (smokers and never-smokers). Respiratory epithelial MMP9 and TIMP mRNA was quantified in 31 severe asthmatics and 32 healthy controls. Sputum MMP-9 activity/TIMP-1 and TIMP-2 ratios, and nasal epithelial MMP9/TIMP1 and MMP9/TIMP2 expression ratios were reduced in smokers with asthma compared with never-smokers with asthma. Low sputum ratios in asthmatic smokers were associated with reduced post-bronchodilator forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity ratio and segmental airway lumen area. The association of a low sputum MMP-9 activity/TIMP-1 ratio with persistent airflow obstruction and reduced CT airway lumen area in smokers with asthma may indicate that an imbalance of MMP-9 and TIMPs contributes to structural changes to the airways in this group. In asthmatic smokers, a low sputum MMP-9 activity/TIMP-1 is associated with spirometric and CT airway narrowing http://ow.ly/wnbAh

Combination of erythromycin and dexamethasone improves corticosteroid sensitivity induced by CSE through inhibiting PI3K-δ/Akt pathway and increasing GR expression

Corticosteroid insensitivity, which is induced by cigarette smoke extract (CSE), is a significant barrier when treating chronic obstructive pulmonary disease (COPD). Erythromycin (EM) has been shown to have an anti-inflammatory role in some chronic airway inflammatory diseases, particularly diffuse panbronchiolitis and cystic fibrosis. Here, we explored whether the combination therapy of EM and dexamethasone (Dex) reverses corticosteroid insensitivity and investigated the molecular mechanism by which this occurs. We demonstrated that the combination of EM and Dex restored corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from COPD patients and U937 cells after CSE exposure. Moreover, pretreatment with 10, 50, or 100 μg/ml EM reversed the HDAC2 protein reduction induced by CSE exposure in a dose-dependent manner. U937 cells exposed to CSE show a reduction in histone deacetylase (HDAC) activity, which was potently reversed by EM or combination treatment. Although 10 and 17.5% CSE increased phosphorylated Akt (PAkt) expression in a concentration-dependent manner, preapplication of EM and the combination treatment in particular blocked this PAkt increase. Total Akt levels were unaffected by CSE or EM treatments. Furthermore, the combination treatment enhanced glucocorticoid receptor (GR)α expression. Our results demonstrate that the combination therapy of EM and Dex can restore corticosteroid sensitivity through inhibition of the PI3K-δ/Akt pathway and enhancing GRα expression.